Interferon-gamma is a T cell-derived cytokine that exhibits anti-viral and immunomodulatory effects on many cell types. Recombinant human interferon-gamma is approved for the treatment of chronic granulomatous disease and severe malignant osteopetrosis. Other indications currently being investigated in human clinical trials include idiopathic pulmonary fibrosis, liver fibrosis, hepatitis C and ovarian cancer. Interferon-gamma has a short half-life after subcutaneous administration that necessitates frequent administration and reduces potential efficacy. We propose to create polymer modified interferon-gamma proteins that can be administered less frequently, but with greater potency, than existing interferon-gamma products. During Phase I we identified sites in interferon-gamma that can be modified with a polyethylene glycol moiety without significantly affecting the protein's in vitro bioactivity. In addition, pharmacokinetic studies were performed in rats to verify that the addition of an inert polymer extends the circulating half-life of interferon gamma. During the Phase II, we will perform more extensive PK studies that evaluate different modes of administration. We will develop methods to produce sufficient quantities of the PEGylated muteins for further testing in animal models and identify the optimum PEGylated interferon-gamma cysteine mutein for commercial development. [unreadable] [unreadable]